of potential variability has developed among the different strains. Over 3 billion doses have been given worldwide, by multiple routes, and BCG has been shown to be an extremely safe vaccine, even in infants. The original route was oral, but in the past 20 or 30 years the intracutaneous route has become more common.

The efficacy of BCG in producing immunity ranges from 0 percent to 100 percent, depending on trial or study. A number of factors have been postulated to explain this variability. Trial methodology varies considerably and makes it difficult to determine the statistical validity of the results. Different strains of BCG were used in the various trials. Different routes and doses may also have contributed to variability. Crossreactive immunity to environmental mycobacteria may have masked or biased the protective effect of the vaccine. Background rates of TB were sometimes too low to show a significant effect.

A 1994 meta-analysis of the published literature on BCG efficacy found that, overall, BCG was 51-percent protective against pulmonary TB, even more effective against disseminated forms of the disease, and 71 percent protective against death. Comparison of 13 prospective trials and 10 case-controlled studies suggested that neither BCG strain nor age at vaccination was an important variable in terms of efficacy. However, geography was important: the further away from the Equator, the higher the efficacy of BCG vaccination. (This may be related to higher endemic rates of environmental mycobacterial colonization and infection in warmer climates.) Study design was also important: the higher the data validity, the higher the efficacy of BCG.

Special Problems in Developing TB Vaccines. Many of the problems with the current vaccine have to do with the special conditions of TB as a disease, rather than with BCG itself. For example, researchers are greatly hampered by their inability to measure infection rates in vaccine trials with BCG. The best way to identify infection is the purified protein derivative (PPD) delayed hypersensitivity test; unfortunately, BCG induces a positive PPD response. In addition, only 10 percent of people that become infected with M. tuberculosis go on to develop disease, and this is often associated with suppression of the immune system. Finally, the long latency of the disease is also a problem; efficacy trials require long-term follow-up, which presents its own difficulties.

It seems obvious that the most important immune response to concentrate on is mycobacteria-specific memory, the only response that could be induced by a vaccine that would persist in vivo and protect against a rechallenge. Much of the in vitro research has not taken this into account. Mycobacteria produce adjuvant-like effects, and it important to have negative lymphocytes as a control or baseline, in order to determine whether an in vitro response is related to memory immune response rather than to an adjuvant or a superantigen-like response that occurs only in vitro.

Four major mycobacteria-specific antigens have been studied as potential vaccine candidates over the past 20 years: